Acrocallosal syndrome

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Acrocallosal syndrome
Polydactyly in a 1 day old infant due acrocallosal syndrome.png
Polydactyly and hallux duplication in a 1-day-old infant due to acrocallosal syndrome.
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg
Symptoms Agenesis of the corpus callosum, craniofacial anomalies, psychomotor retardation with hypotonia, polydactyly
DurationLifelong
CausesMutations in KIF7 or GLI3
FrequencyFewer than 50 cases [1] [2]

Acrocallosal syndrome (also known as ACLS) is an extremely rare autosomal recessive syndrome characterized by corpus callosum agenesis, polydactyly, multiple dysmorphic features, motor and intellectual disabilities, and other symptoms. [3] The syndrome was first described by Albert Schinzel in 1979. [4] Mutations in KIF7 are causative for ACLS, and mutations in GLI3 are associated with a similar syndrome. [5]

Contents

Signs and symptoms

Acrocallosal syndrome (ACLS, ACS, Schinzel-type, Hallux-duplication) is a rare, heterogeneous [5] autosomal recessive disorder first discovered by Albert Schinzel (1979) in a 3-year-old boy. [4] Characteristics of this syndrome include agenesis of the corpus callosum, macrocephaly, hypertelorism, poor motor skills, intellectual disability, extra fingers and toes (particularly hallux duplication), and cleft palate. Seizures may also occur. [2]

Mechanism

This disease is autosomal recessive. Autosomal recessive - en.svg
This disease is autosomal recessive.

Mutations in the KIF7 gene are causative for ACLS. KIF7 is a 1343 amino acid protein with a kinesin motor, coiled coil, and Gli-binding domains. It is associated with ciliary motor function [5] and is a key factor in the ciliary Hedgehog signaling pathway that is crucial during embryogenesis. Mutations in Hedgehog signaling components such as KIF7 and GLI3 may lead to ciliopathies and defects in the brain and other areas associated with ACLS and related disorders. [6]

Mutations in the GLI3 gene may cause ACLS or similar syndromes such as Greig cephalopolysyndactyly syndrome, Pallister–Hall syndrome, or certain types of polydactyly. KIF7 interacts with Gli transcription factors, so mutations in the KIF7 gene may be upstream effectors of GLI3, resulting in similar symptoms. [7]

Diagnosis

ACLS is typically diagnosed on the basis of physical examination. At least three of four core criteria published by Courtens et al. (1997) [8] must be present: [2]

  1. Total or partial agenesis of the corpus callosum
  2. Minor craniofacial anomalies such as macrocephaly or hypertelorism
  3. Moderate to severe psychomotor retardation with hypotonia
  4. Polydactyly

The differential diagnosis includes Greig cephalopolysyndactyly syndrome, orofaciodigital syndrome types I and II, Meckel–Gruber syndrome, Smith–Lemli–Opitz syndrome, Rubinstein–Taybi syndrome, Cockayne syndrome, Aicardi syndrome, Neu–Laxova syndrome, Young–Madders syndrome, oto-palato-digital syndrome type 2, Toriello–Carey syndrome, and Da Silva syndromes. [2] ACLS may be differentiated from Greig cephalopolysyndactyly syndrome by the presence of intracranial cysts. [9]

ACLS may be suspected antenatally if a previous child is affected, as any subsequent child has a 25% chance of having ACLS. Obstetric ultrasonography or magnetic resonance imaging can reveal polydactyly and/or cerebral malformations from the 20th week of gestation. [10] Chorionic villus sampling and molecular genetic testing can be performed to confirm whether mutations in disease-associated genes are present. [2]

ACLS is an extremely rare disorder, with 34 cases described in the literature as of 2005. [1]

Management

Management of ACLS consists mainly of monitoring by a pediatric neuropsychiatrist and supportive therapies or accommodations such as occupational therapy and special education plans. Surgery may be considered in early childhood to remove extra digits in case of polydactyly or resolve orofacial defects such as cleft palate. If present, seizures and renal parenchymal hypertension may be treated with anticonvulsants and antihypertensive drugs, respectively. Patients may be offered genetic and vocational counselling when appropriate. [10]

Prognosis

Lifespan may range from stillbirth to normal expectancy depending on severity of hypotonia and onset of epilepsy. [4] Severe hypotonia can lead to fatal infant respiratory distress syndrome or apnea within the first days or weeks of life. [9] [10] Conversely, in mild cases, subjects live relatively normal lives with some developmental delays and mild to moderate intellectual disability. [4] [10]

Related Research Articles

<span class="mw-page-title-main">Joubert syndrome</span> Medical condition

Joubert syndrome is a rare autosomal recessive genetic disorder that affects the cerebellum, an area of the brain that controls balance and coordination.

<span class="mw-page-title-main">Macrocephaly</span> Abnormally large head size

Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to determine whether the syndrome is accompanied by particular disorders. Those with benign or familial macrocephaly are considered to have megalencephaly.

<span class="mw-page-title-main">MASA syndrome</span> Medical condition

MASA syndrome is a rare X-linked recessive neurological disorder on the L1 disorder spectrum belonging in the group of hereditary spastic paraplegias a paraplegia known to increase stiffness spasticity in the lower limbs. This syndrome also has two other names, CRASH syndrome and Gareis-Mason syndrome.

Agenesis of the corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum. It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres in the brain, in the embryo is disrupted. The result of this is that the fibers that would otherwise form the corpus callosum are instead longitudinally oriented along the ipsilateral ventricular wall and form structures called Probst bundles.

<span class="mw-page-title-main">GLI3</span> Protein-coding gene in the species Homo sapiens

Zinc finger protein GLI3 is a protein that in humans is encoded by the GLI3 gene.

<span class="mw-page-title-main">Greig cephalopolysyndactyly syndrome</span> Medical condition

Greig cephalopolysyndactyly syndrome is a disorder that affects development of the limbs, head, and face. The features of this syndrome are highly variable, ranging from very mild to severe. People with this condition typically have one or more extra fingers or toes (polydactyly) or an abnormally wide thumb or big toe (hallux).

<span class="mw-page-title-main">Pallister–Hall syndrome</span> Medical condition

Pallister–Hall syndrome (PHS) is a rare genetic disorder that affects various body systems. The main features are a non-cancerous mass on the hypothalamus and extra digits (polydactylism). The prevalence of Pallister-Hall Syndrome is unknown; about 100 cases have been reported in publication.

3C syndrome is a rare condition whose symptoms include heart defects, cerebellar hypoplasia, and cranial dysmorphism. It was first described in the medical literature in 1987 by Ritscher and Schinzel, for whom the disorder is sometimes named.

Vici syndrome, also called immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum, is a rare autosomal recessive congenital disorder characterized by albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, severe psychomotor retardation, seizures, immunodeficiency and recurrent severe infections. To date, about 50 cases have been reported.

<span class="mw-page-title-main">Ciliopathy</span> Genetic disease resulting in abnormal formation or function of cilia

A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem. The similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual genetic cause, it is clustering of a set of characteristic physiological features which define whether a syndrome is a ciliopathy.

FG syndrome (FGS) is a rare genetic syndrome caused by one or more recessive genes located on the X chromosome and causing physical anomalies and developmental delays. FG syndrome was named after the first letters of the surnames of the first patients noted with the disease. First reported by American geneticists John M. Opitz and Elisabeth G. Kaveggia in 1974, its major clinical features include intellectual disability, hyperactivity, hypotonia, and a characteristic facial appearance including macrocephaly.

<span class="mw-page-title-main">Lujan–Fryns syndrome</span> Medical condition

Lujan–Fryns syndrome (LFS) is an X-linked genetic disorder that causes mild to moderate intellectual disability and features described as Marfanoid habitus, referring to a group of physical characteristics similar to those found in Marfan syndrome. These features include a tall, thin stature and long, slender limbs. LFS is also associated with psychopathology and behavioral abnormalities, and it exhibits a number of malformations affecting the brain and heart. The disorder is inherited in an X-linked dominant manner, and is attributed to a missense mutation in the MED12 gene. There is currently no treatment or therapy for the underlying MED12 malfunction, and the exact cause of the disorder remains unclear.

<span class="mw-page-title-main">Sotos syndrome</span> Genetic overgrowth disorder

Sotos syndrome is a rare genetic disorder characterized by excessive physical growth during the first years of life. Excessive growth often starts in infancy and continues into the early teen years. The disorder may be accompanied by autism, mild intellectual disability, delayed motor, cognitive, and social development, hypotonia, and speech impairments. Children with Sotos syndrome tend to be large at birth and are often taller, heavier, and have relatively large skulls (macrocephaly) than is normal for their age. Signs of the disorder, which vary among individuals, include a disproportionately large skull with a slightly protrusive forehead, large hands and feet, large mandible, hypertelorism, and downslanting eyes. Clumsiness, an awkward gait, and unusual aggressiveness or irritability may also occur.

<span class="mw-page-title-main">Andermann syndrome</span> Medical condition

Andermann syndrome, also known as agenesis of corpus callosum with neuronopathy (ACCPN) and Charlevoix disease, among other names, is a very rare neurodegenerative genetic disorder that damages the nerves used to control muscles and related to sensation and is often associated with agenesis of the corpus collosum.

Toriello–Carey syndrome is a genetic disorder that is characterized by Pierre Robin sequence and agenesis of the corpus callosum. Children with the disorder also possess a characteristic facial phenotype.

<span class="mw-page-title-main">Chudley–Mccullough syndrome</span> Medical condition

Chudley–Mccullough syndrome is a rare genetic disorder which is characterized by bilateral congenital hearing loss associated with brain malformations. It is a type of syndromic deafness.

Proud syndrome is a very rare genetic disorder which is characterized by severe intellectual disabilities, corpus callosum agenesis, epilepsy, and spasticity. It is a type of syndromic X-linked intellectual disability.

Holoprosencephaly-ectrodactyly-cleft lip/palate syndrome, also simply known as Hartsfield syndrome, is a rare genetic disorder characterized by the presence of variable holoprosencephaly, ectrodactyly, cleft lip and palate, alongside generalized ectodermal abnormalities. Additional findings include endocrine anomalies and developmental delays.

<span class="mw-page-title-main">Severe intellectual disability-progressive spastic diplegia syndrome</span> Medical condition

Severe intellectual disability-progressive spastic diplegia syndrome is a rare novel genetic disorder characterized by severe intellectual disabilities, ataxia, craniofacial dysmorphisms, and muscle spasticity. It is a type of autosomal dominant syndromic intellectual disability.

References

  1. 1 2 "European Conference on Rare Diseases" (PDF). European organisation for Rare Diseases. June 21–22, 2005. p. 35. Retrieved 2021-12-05.
  2. 1 2 3 4 5 "Acrocallosal syndrome, Schinzel type". Genetic and Rare Diseases Information Center. NIH National Center for Advancing Translational Sciences. Retrieved 2021-12-05.
  3. Online Mendelian Inheritance in Man (OMIM): Acrocallosal syndrome; ACLS - 200990
  4. 1 2 3 4 Schinzel, Albert (May 1979). "Postaxial polydactyly, hallux duplication, absence of the corpus callosum, macroencephaly and severe mental retardation: a new syndrome?". Helvetica Paediatrica Acta. 34 (2): 141–6. PMID   457430.
  5. 1 2 3 Elson E, Perveen R, Donnai D, Wall S, Black GC (November 2002). "De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models". J. Med. Genet. 39 (11): 804–6. doi:10.1136/jmg.39.11.804. PMC   1735022 . PMID   12414818.
  6. Walsh D.; Shalev S.; Simpson M.; Morgan N.; Gelman-Kohan Z.; Chemke J.; Trembath R.; Maher E. (2013). "Acrocallosal syndrome: Identification of a novel KIF7 mutation and evidence for oligogenic inheritance". European Journal of Medical Genetics. 56 (1): 39–42. doi:10.1016/j.ejmg.2012.10.004. PMID   23142271.
  7. Putoux, Audrey; Thomas, Sophie; Coene, Karlien L M; Davis, Erica E; Alanay, Yasemin; Ogur, Gönül; Uz, Elif; Buzas, Daniela; Gomes, Céline (2013-06-06). "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes". Nature Genetics. 43 (6): 601–606. doi:10.1038/ng.826. ISSN   1061-4036. PMC   3674836 . PMID   21552264.
  8. Courtens W, Vamos E, Christophe C, Schinzel A (1997). "Acrocallosal syndrome in an Algerian boy born to consanguineous parents: review of the literature and further delineation of the syndrome". Am J Med Genet. 69 (1): 17–22. doi:10.1002/(sici)1096-8628(19970303)69:1<17::aid-ajmg4>3.0.co;2-q. PMID   9066878.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. 1 2 Koenig R.; Bach A.; Ulrike W.; Grzeschik K-H; Fuchs S. (2002). "Spectrum of the acrocallosal syndrome". American Journal of Medical Genetics. 108 (1): 7–11. doi:10.1002/ajmg.10236. PMID   11857542.
  10. 1 2 3 4 Ramteke VV, Darole PA, Shaikh ZF, Padwal NJ, Agrawal B, Shrivastava MS; et al. (2011). "Acrocallosal syndrome in a young hypertensive male". BMJ Case Rep. 2011: bcr1220103648. doi:10.1136/bcr.12.2010.3648. PMC   3089937 . PMID   22696705.{{cite journal}}: CS1 maint: multiple names: authors list (link)